Cost-Effectiveness of Tamsulosin, Doxazosin, and Terazosin in the Treatment of Benign Prostatic Hyperplasia

OBJECTIVES: To evaluate the cost-effectiveness of tamsulosin, doxazosin, or terazosin as initial treatments for moderate benign prostatic hyperplasia (BPH) over a 3-year time horizon from a health-system-payer perspective. METHODS: A decision-analytic model is used to project the course of treatment at 6-month intervals over 3 years following initiation of therapy with tamsulosin, doxazosin, or terazosin. Treatment failure is defined as failure to attain and maintain a 25% improvement in the American Urological Association (AUA) symptom score from baseline. In the model, finasteride is added for patients who fail on their initial therapy and, in the event of finasteride treatment failure, patients progress to transurethral resection of the prostate (TURP) and, if needed, a second TURP. The ranges of values for treatment failure rates and clinical event cost parameters used in the decision model are derived from the literature. Only direct medical costs related to BPH and its treatment are included. Since 2 comparators are available generically (doxazosin and terazosin) drug acquisition costs are defined by the list prices at Drugstore.com. All costs are discounted by 3% per year. Effectiveness is measured as successful medical treatment without surgery over 3 years. RESULTS: For base-case model parameters, discounted BPH-related total direct medical costs over 3 years are $4084, $4323, and $4695 for generic terazosin, generic doxazosin, and tamsulosin, respectively. The model estimates a medical treatment success rate (no TURP) at 3 years of 72.3% for tamsulosin, compared with 68.2% for both terazosin and doxazosin. The incremental cost for tamsulosin versus terazosin is $610 over 3 years, which yields an incremental cost-effectiveness ratio of $14,609 per success. Generic doxazosin is dominated (higher cost but equal effectiveness compared with terazosin). Higher rates of twice daily (or 2 units per day) dosing are associated with higher incremental cost effectiveness ratios. The decision-model results also are sensitive to the estimated costs of TURP and hypotensive adverse events. CONCLUSIONS: As an initial medical therapy for moderate BPH, tamsulosin is more effective than generic terazosin or doxazosin, with an incremental cost of about $203 per year (or about $17 per month) over 3 years.

enign prostatic hyperplasia (BPH) is a common and costly condition in the United States. Nearly 50% of men aged 50 years or older report symptoms of BPH, and prevalence increases with advancing age. 1 As the U.S. population ages, the incidence of BPH will continue to grow. In addition to increasing incidence of BPH, patterns of treatment for BPH also are evolving, with movement from primarily surgical treatment (open prostatectomy and transurethral resection of the prostate [TURP] as well as newer, less invasive options) toward medical management of BPH symptoms. Surgery rates have decreased since alpha (α)-antagonists and 5α-reductase inhibitors became available to treat BPH. [2][3][4] Several pharmacoeconomic studies have evaluated the use of α-antagonists in the treatment of BPH. These analyses have demonstrated that α-antagonists have the potential to decrease costs relative to surgical interventions. 5,6 In addition, compared with placebo, α-antagonists have the ability to relieve symptoms without increasing overall health care costs by reducing costs for hospitalizations and outpatient visits. Overall cost-effectiveness for the different treatments may vary depending on individual patient characteristics and comorbid conditions.
Pharmacoeconomic analyses of new treatment options for BPH are useful in view of the increased attention being placed on treatment costs and the increasing incidence of BPH. Because several established BPH treatments are available (each with a different mechanism of action, effectiveness rate, safety profile, and associated cost), consideration of cost-effectiveness analyses can help to quantify potential advantages of new treatment options to facilitate treatment choices.
Tamsulosin (Flomax), an α 1A -selective antagonist, was approved by the U.S. Food and Drug Administration on April 15, 1997, for the medical management of BPH. 7 Tamsulosin is prostate-specific and has reduced affinity for α-receptors in the peripheral vasculature. As such, tamsulosin has several characteristics that may lead to increased cost-effectiveness, including a favorable side-effect profile and less dosage titration compared with older generation nonselective α1-antagonists. Specifically, side effects of nonselective α1-antagonists, including orthostatic hypotension and syncope, can reduce patient adherence to medical therapy, thereby reducing effectiveness and increasing costs. The use of the α 1A -selective antagonist tamsulosin is associated with substantially lower rates of orthostatic symptoms than nonselective α 1 -antagonists. For example, Wilt et al. 8 report that 9.3% of patients treated with terazosin experienced orthostatic hypotension versus 1% in the control groups ABSTRACT OBJECTIVE: To evaluate the cost-effectiveness of tamsulosin, doxazosin, or terazosin as initial treatments for moderate benign prostatic hyperplasia (BPH) over a 3-year time horizon from a health-system-payer perspective.
METHODS: A decision-analytic model is used to project the course of treatment at 6-month intervals over 3 years following initiation of therapy with tamsulosin, doxazosin, or terazosin. Treatment failure is defined as failure to attain and maintain a 25% improvement in the American Urological Association (AUA) symptom score from baseline. In the model, finasteride is added for patients who fail on their initial therapy and, in the event of finasteride treatment failure, patients progress to transurethral resection of the prostate (TURP) and, if needed, a second TURP. The ranges of values for treatment failure rates and clinical event cost parameters used in the decision model are derived from the literature. Only direct medical costs related to BPH and its treatment are included. Since 2 comparators are available generically (doxazosin and terazosin) drug acquisition costs are defined by the list prices at Drugstore.com. All costs are discounted by 3% per year. Effectiveness is measured as successful medical treatment without surgery over 3 years.
RESULTS: For base-case model parameters, discounted BPH-related total direct medical costs over 3 years are $4084, $4323, and $4695 for generic terazosin, generic doxazosin, and tamsulosin, respectively. The model estimates a medical treatment success rate (no TURP) at 3 years of 72.3% for tamsulosin, compared with 68.2% for both terazosin and doxazosin. The incremental cost for tamsulosin versus terazosin is $610 over 3 years, which yields an incremental cost-effectiveness ratio of $14,609 per success. Generic doxazosin is dominated (higher cost but equal effectiveness compared with terazosin). Higher rates of twicedaily (or 2 units per day) dosing are associated with higher incremental costeffectiveness ratios. The decision-model results also are sensitive to the estimated costs of TURP and hypotensive adverse events.
(P<0.01) across trials reporting this adverse event. Similarly, Kirby et al. 9 report that 5.1% of patients treated with doxazosin experienced hypotension versus 1.5% in the placebo group (P<0.05). In contrast, Lepor et al. 10 report that 0.6% of patients treated with tamsulosin experienced orthostatic hypotension versus none in the placebo group (no P value reported). With its advantageous safety profile, tamsulosin may reduce the complications and lead to greater overall cost-effectiveness. However, to date, no formal pharmacoeconomic evaluation of the cost-effectiveness of tamsulosin has been published.
ss Background A number of cost-effectiveness evaluations of alternative treatment strategies for BPH have been published. Most of these have been summarized in several literature review papers. 5,6,11 Although none of these published analyses evaluate the costeffectiveness of tamsulosin as a treatment strategy for BPH, highlighting the findings in some of these prior studies provides context for the present study.
One of the first attempts to quantify short-term comparative costs of standard surgical interventions and medical therapies for BPH was published in 1994 by the Agency for Health Care Policy and Research (AHCPR) as part of the final report for the Prostate Patient Outcomes Research Team (Prostate PORT) project. 12 The model compared total costs for 2 years of treatment for each of the following initial therapies: watchful waiting, drug therapy (finasteride or α-blocker), balloon dilation, TURP, and open prostatectomy. Estimated costs of secondary treatments, if necessary, were factored into the estimates for the primary treatments as were the estimated costs for surgical complications.
The AHCPR model results indicated that the most costly initial treatment was open prostatectomy, followed by TURP, balloon dilation, medical therapy, and watchful waiting. Costs for finasteride and α-blockers were similar. Surgical options were estimated to cost approximately 5 times as much as drug therapy during the 2-year duration of the model, thus demonstrating the ability of medical treatments to decrease the cost of care for BPH patients-at least over the short term. The model assumed all patients with medical treatment failures were assumed to proceed to TURP whereas in usual clinical practice, many of these patients may elect watchful waiting or an alternative medication. The authors acknowledged that this model assumption might overestimate costs for medical treatments. As a result, drug therapy may have the potential to decrease costs compared with surgical interventions to an even greater extent than estimated in the model.
Another model, taking the perspective of the U.S. military, compared finasteride to α 1 -antagonists (prazosin, doxazosin, and terazosin) for the initial medical treatment of BPH. 13 In the model, patients were started on drug therapy only after failing an initial period of watchful waiting. Patients who failed the initial medical therapy were assumed to switch to an alternative medication with up to 2 TURP procedures as needed to maintain treatment success. The duration of the analysis was 36 months. The model results indicated that prazosin, the α 1 -antagonist with the lowest acquisition cost, would be the most cost-effective therapy (lowest cost per successfully treated patient). However, an important limitation of the model is the assumption of equal patient compliance rates and equal effectiveness rates with each α 1 -antagonist, despite twice-daily dosing required for prazosin compared with daily dosing for the other α 1 -antagonists.
A recent cost-utility model compared treatment with transurethral microwave thermotherapy with drug treatment with α-blockers or surgical treatment with TURP for men with moderate-to-severe BPH. 14 Utilities for health states for BPH and the alternative treatments were defined for less risk-averse and more risk-averse patients. In the decision model, patients who failed initial therapy were switched to alternative therapies, including watchful waiting. Specific switch distributions for each initial therapy were determined by an expert panel.
Over 5 years, the projected costs were lowest for patients treated with medical therapy ($6,294) and highest for TURP ($7,334), with intermediate costs for thermotherapy ($7,035). However, thermotherapy had the highest projected qualityadjusted life-months over 5 years (53.52, compared with 53.29 for medical therapy and 51.81 for TURP). This translates into an incremental cost per quality-adjusted life-year (QALY) of about $39,000 for thermotherapy compared with drug therapy with α-blockers. Qualitatively similar results were obtained when the analysis was replicated using utilities for more riskaverse patients.
To develop a cost-effectiveness model appropriate for an economic evaluation of tamsulosin compared with other treatment options, it is important to capture the most important elements of alternative initial treatments as they affect usual clinical practice, while retaining conceptual transparency and computational feasibility in the model. Given the absence of dramatic differences in the efficacy of alternative α-blocker therapies for BPH as revealed in clinical trials, differences in cost-effectiveness across these drugs will be attributable primarily to differences in drug acquisition costs and differences in the profiles of alternative drug therapies in terms of treatment complexity (dosage frequency, titration) and rates of adverse events (AEs), and tolerability.
Both tamsulosin and the less selective α 1 -blockers doxazosin and terazosin typically are administered once daily. However, doxazosin and terazosin usually are initially prescribed at a subtherapeutic dose, with the dose slowly increased over a 2-to-4-week period until a full therapeutic maintenance dose is reached. Initial dosage adjustment is not needed with tamsulosin because treatment may be initiated at the usual daily maintenance dose. 15 In terms of tolerability, the literature suggests several potential advantages for tamsulosin. Of the α 1 -selective agents, only tamsulosin is considered to be "prostate specific." Because of its reduced effect on receptor subtypes found in the peripheral vasculature (α-1b), tamsulosin generally is associated with lower rates of AEs in the form of orthostatic hypotension, asthenia, and syncope. As noted in Lepor et al., 10 in U.S. trials of 0.4 mg tamsulosin daily versus placebo, the rate of postural hypotension was 0.2% (1 of 502) in the treatment group and zero in the placebo group. Syncope was reported by 0.2% (1 of 502) of patients in the treatment group and 0.6% (3 of 493) of patients taking placebo. In contrast, in Kirby et al., 9 the rate of postural hypotension was 5.8% in the doxazosin group and 1.5% in the placebo group (P<0.05). As reported in Wilt et al., 8 across placebo-controlled trials, patients taking terazosin were much more likely to experience postural hypotension (RR = 5.27, P<0.01). As Speakman 16 conjectures, the higher adverse event rates observed in older α-blockers may adversely affect patient adherence to therapy, thereby reducing effectiveness. The management of these AEs also may contribute directly to overall treatment costs as well as directly affecting health-related quality of life.
A recent retrospective cohort study assessed the occurrence of hypotensive-related events, including falls and fractures, associated with use of terazosin, doxazosin, and prazosin. 17 Using prescription drug and medical utilization claims data from a retiree health plan, Chrischilles and colleagues evaluated the incidence of hypotensive events among men aged 65 years or older with and without hypertension. Potential hypotensive events included syncope, postural hypotension, vertigo, fractures, and other injuries as indicated in the claims data. Rates of possible hypotensive events were compared before and after drug initiation in men with a diagnosis of BPH who began therapy with terazosin, doxazosin, or prazosin during the study period (January 1995 through December 1997). The effects of age, presence or absence of hypertension, and risk factors for hypertensive events were controlled for in the analysis. Data for 1,277 men were evaluated (211 with a diagnosis of hypertension The results indicated that the risk of these hypotensive-related events increased after the initiation of non-prostate-specific α-blockers for BPH treatment. For example, among men without hypertension, there was a 1.1% excess incidence of fractures, with fractures of the hip or pelvis accounting for 54% of all fractures.
In contrast, several studies have confirmed that tamsulosin has negligible effects on blood pressure and does not cause clinically meaningful orthostatic changes. 10,18,19 These negligible effects indicate that the medical services and costs associated with blood pressure monitoring and treatment of blood pressure-related side effects can be minimized. These lower costs may work to offset the higher drug acquisition costs for tamsulosin compared with the older α 1 -antagonists, all now available as generic drugs.
ss Pharmacoeconomic Methods

Model Structure
The basic structural elements of the decision model used to evaluate the cost-effectiveness of tamsulosin are illustrated in Figure 1. Treatment is initiated with tamsulosin, terazosin, or doxazosin. Terazosin and doxazosin were selected as α 1 -antagonists comparators with tamsulosin because they generally are prescribed for once-daily dosing, as is tamsulosin. Prazosin was not included because it generally is prescribed for twice-daily dosing and, in current practice, is rarely used to treat BPH. 17 Patients at initiation are defined as newly diagnosed (treatment naïve) or patients who have failed "watchful waiting" who have American Urological Association (AUA) symptom scores in the moderate range at baseline. After initiation of therapy, over the initial 6 months, the therapy is either successful or unsuccessful, where treatment success is defined as a 25% improvement in AUA symptom score from baseline. If the initial therapy is successful at 6 months, the patient continues on the therapy for another 6 months. If the initial therapy is successful at the end of 12 months, the patient continues on the therapy for another 6 months, and so on, for 3 years. However, if the initial therapy fails, subsequent therapy is modified.
A 25% improvement from baseline AUA symptom score is a commonly specified end point in clinical trials of drug therapies for BPH. Other common end points include the absolute change in AUA symptom score, change in mean peak urinary flow rate, and postvoid urine retention. The model focuses on the percentage achieving a 25% or better improvement in AUA symptom score for several reasons. First, this outcome metric corresponds to a clinically relevant concept of "treatment success" for patients with moderate BPH symptoms that fits naturally within a clinical decision-model framework. In other words, the model assumes that modifications in treatment are triggered by lack of treatment success rather than specific values of clinical parameters. Second, the various outcome measures tend to be highly correlated. Though we have not evaluated a model using different clinical end points and more complex decision rules, the model presented here should provide a reasonable representation of expected outcomes in usual clinical practice.
A therapy may fail for a variety of reasons. In some cases, the desired result is not obtained despite appropriate use, but, in many cases, failure is related to discontinuation of use-either due to AEs or other reasons. If the initial drug therapy has to be discontinued due to an AE, the patient is switched to finasteride (monotherapy). If the initial therapy "fails" for any other reason, finasteride is added to the initial therapy (combination therapy). If the new therapy is successful at the end of a 12-month period, the patient remains on the new therapy. This 12-month (versus 6-month) window follows Cockrum et al. 13 and is based on the slower onset of effect for finasteride compared with α-blockers. If the new (monotherapy or combination) drug therapy fails, the patient then progresses to TURP. If the TURP is not successful (in terms of AUA symptom score improvement), the patient has a repeat TURP. However, patients undergoing TURP also are at risk for permanent AEs of TURP, such as incontinence or impotence.
Two alternative treatment pathways following initial therapy failure are evaluated in the model. The first assumes an immediate switch to finasteride in all cases (no combination therapy). The second assumes a switch to tamsulosin in the event of discontinuation of doxazosin or terazosin due to hypotensive AEs, with finasteride subsequently added in the event of therapeutic failure (intermediate switch to tamsulosin). This second pathway only affects initial treatment strategies using doxazosin or terazosin.
Three effectiveness measures are employed in the decision model. The first definition of effective therapy is treatment success at 3 years without the need for TURP. This is labeled "successful medical therapy" and will be the primary measure used in the analysis. Two alternative effectiveness measures are used. A less restrictive measure of effectiveness is treatment success at 3 years without permanent TURP-related complications. A more restrictive measure is treatment success at 3 years on the initial drug therapy without switching drugs or adding finasteride ("initial therapy success").
Patients initiating any therapy will be at risk for any AEs associated with therapy. The specific types of AEs and levels of risk are related to the specific therapy evaluated. AEs, when they occur, have 2 implications in the model. First, some AEs, such as hypotension, may directly generate excess resource utilization and costs, thereby increasing overall treatment costs. Second, as noted, AEs may require a modification of therapy, with increased medical management costs. The occurrence of minor AEs also may affect patient decisions to persist on therapy, which may affect both the cost and effectiveness of therapy. All of these model events have some impact on the costs of treatment for patients initiating a specific therapy. The model  accumulates these costs for patients along each potential treatment path, thus allowing for comparison of total treatment costs across the 3 initial therapies. Incremental cost-effectiveness ratios (ICERs) may be derived from the total cost and effectiveness measures.

Model Parameters
Specific values for model parameters used for the base-case analysis are reported in Table 1. The first set of model parameters relate to the clinical efficacy of each of the 3 initial therapies. Based on AHCPR meta-analysis, the initial treatment efficacy was assumed to be 74% for terazosin and doxazosin. Following Lepor et al., 19 initial treatment efficacy was assumed to be 81% for tamsulosin. To translate these initial efficacy estimates into initial effectiveness estimates, an additional discontinuation factor (above that observed in clinical trials) is used. It is possible that the tolerability advantages of tamsulosin over the non-prostate-specific α 1 -blockers translate into greater adherence to therapy in actual clinical practice. However, there are no published studies with analyses of data from usual clinical practice to confirm this possibility. The base-case model assumes an additional 10% discontinuation rate for all drug therapies in the initial period, with a range of 5% to 20% evaluated in sensitivity analyses. Another factor that may affect both effectiveness and cost is the percentage of users for each drug with twice-daily compared with once-daily dosing. Although twice-daily dosing is not recommended for any of these drugs for the treatment of BPH, Raymond and Smith 20 found twice-daily use rates of 17% for terazosin and 38% for doxazosin in usual clinical practice. However, the patient sample used in the study includes both hypertensive and normotensive patients with BPH. Thus, it is possible that all twice-daily use is among BPH patients using these drugs to treat comorbid hypertension. To be conservative, the base-case model assumes no twice-daily use among BPH patients for any of the 3 drugs.
If twice-daily dosing is prescribed for terazosin or doxazosin as treatment of BPH, it may represent an effort to minimize the risk of hypotensive events. In the case of tamsulosin, 0.8 mg once-daily dosing (two 0.4 mg capsules) is recommended in the prescribing information for patients who do not respond to the 0.4 mg dose in the initial 2 to 4 weeks of therapy. Values of 5% to 20% twice-daily use are considered in sensitivity analyses, which is 0.2x to 0.7x the average rate observed in Raymond and Smith. 20 For consistency, the same rates of use of 2 units per day are assumed for tamsulosin.
The extent of twice-daily or 2 units per day dosing has a direct impact on costs because drug acquisition costs per pill for doxazosin and terazosin are approximately the same for all dosage strengths. Therefore, when it occurs, twice-daily or 2 units per day dosing is associated with about twice the drug acquisition costs compared with 1 unit per day dosing. A study by Paes and colleagues 21 suggests that twice-daily dosing is associated with lower rates of adherence to therapy than oncedaily dosing. Thus, the use of twice-daily dosing could impact effectiveness compared with once-daily dosing. This potential effect is captured in the model by assuming that the reduction in effectiveness associated with discontinuation or nonadherence for twice-daily dosing is 1.33 times the reduction for once-daily dosing.
Drug-induced hypotension also can have direct cost effects. Chrischilles and colleagues 17 found excess rates of resource utilization among new users of non-prostate-specific α 1 -blockers consistent with hypotensive episodes-often sprains and fractures associated with falls. The distribution of diagnosis codes in these cases was used to estimate the cost per excess fracture and nonfracture episode. Higher and lower cost-per-case estimates are used in sensitivity analysis.
The need for titration also can affect costs due to the more intensive effort required to manage medical therapy. In the model, patients who initiate therapy with terazosin are assumed to begin with 2 mg for 10 days, then go to 5 mg for 10 days and 10 mg per day thereafter. Patients who initiate therapy with doxazosin are assumed to begin with 4 mg for 10 days and then go to 8 mg per day thereafter. These titration schedules are more rapid and entail fewer steps than in most previously published models (e.g., Cockrum et al. 13 ), as these less conservative titration schedules are more likely to be consistent with usual practice (based on clinical judgment [Chrischilles and Kreder]). In contrast, patients initiating therapy with tamsulosin are assumed to take 0.4 mg once daily with no titration in the base-case model.
Base-case drug acquisition cost estimates are real-world prices as listed on Drugstore.com. 22 The posted price for a 30-day supply was used to estimate unit prices for all dosage strengths. An alternative estimate of drug acquisition costs was used in sensitivity analyses based on average wholesale prices (AWP) for each of the dosage strengths for each of the drugs, less an assumed discount/rebate of 20% for brand-name drugs and 50% for generic drugs. AWP prices were obtained from the "Red Book." 23 For the brand-name drugs (tamsulosin and finasteride), there is only 1 AWP. However, both of the generic drugs have several different manufacturers with differing AWPs. For doxazosin, this is a minor issue since most of the generic AWPs are similar, but for terazosin, there was considerable variation in AWPs across manufacturers. To be conservative, AWP estimates for the generic drugs are based on the 5 lowest-price manufacturers in terms of AWP. The resulting estimate may be lower than a market-share weighted average AWP, particularly for terazosin.
Estimates of unit costs for various resources used in the treatment of BPH were obtained from the literature, primarily as summarized by Cockrum et al. 13 and Ackerman et al. 24 Estimates of rates of complications for TURP were obtained from several sources, 12,25-28 as noted in Table 1. The estimated cost for TURP used in the base case is an incidence-rate weighted average of costs associated with various surgical complications of TURP.
The model considers all direct medical costs regardless of source of payment. As such, the perspective might be described as a payer perspective for any payer responsible for all (or virtually all) direct medical costs. As part of the sensitivity analysis, an alternative model excludes usual patient drug copays from total cost. All costs are expressed in 2003 dollars and are discounted using a discount rate of 3%.

ss Results
The model results for the base-case model parameters are presented in Table 2. For the base-case treatment path (top panel), the estimated total discounted direct cost associated with BPH treatment over 3 years after initiating therapy are reported in the first column: $4,084 for generic terazosin, $4,323 for generic doxazosin, and $4,695 for tamsulosin. Using medical treatment success (no TURP) at 3 years as the primary effectiveness measure, the base-case model predicts that medical success is achieved for 68.2% of patients initiating therapy with terazosin or doxazosin compared with 72.3% for tamsulosin (column 2). Similar patterns hold for alternative measures of effectiveness. For example, successful medical therapy with the initial drug therapy at 3 years is achieved for 54.7% of patients initiating therapy with either terazosin of doxazosin compared with 60.7% for tamsulosin (not shown in table).
If the base-case treatment path is altered such that all patients who "fail" initial therapy are switched to finasteride (instead of being added to the initial therapy for patients who did not discontinue initial therapy due to AEs or other reasons), effectiveness is reduced for all 3 initial treatment strategies (middle panel). However, 3-year discounted costs are relatively unaffected. If patients who discontinue doxazosin or terazosin due to hypotensive events are switched to tamsulosin as an intermediate step in the treatment pathway (bottom panel), costs for terazosin and doxazosin are slightly lower than in the base-case pathway, and effectiveness is improved.
The incremental cost per medical treatment success for initial therapy with tamsulosin is $14,609 compared with initial terazosin therapy for the base-case pathway (column 5). Initial therapy with doxazosin is dominated as an initial treatment strategy (higher cost but equal effectiveness compared with terazosin). This is due to the lower drug acquisition costs for terazosin. If the treatment pathway excludes combination therapy with finasteride, the incremental cost per medical treatment success is $8,310 for tamusulosin compared with terazosin. If patients who fail doxazosin or terazosin due to hypotensive AEs are switched to tamsulosin first, the estimated incremental cost per medical treatment success is $34,902 for tamsulosin versus terazosin. However, this result should be interpreted with considerable caution because the improvement in effectiveness for terazosin when effectiveness is defined as medical success primarily results from an additional medication trial period in the treatment path. This additional drug trial period delays potential progression to TURP by at least 1 cycle for those patients experiencing hypotensive AEs while taking terazosin. As shown in Table 3, this is particularly evident for the most expansive definition of treatment success-success without serious TURP-related complications. In contrast, it has no effect on incremental effectiveness for the most restrictive definition of treatment success-success on initial drug therapy.
If all 3 treatment paths are considered in a single incremental cost-effectiveness analysis using medical success as an effectiveness metric (Table 4), there are only 2 nondominated strategies: initial therapy with terazosin with an intermediate switch to tamsulosin (lowest cost) and tamsulosin for the base-case treatment path (most effective).
Model results for several sensitivity analyses are summarized in Table 5. Reducing the assumed initial treatment efficacy from base-case values by 20% increases incremental cost and reduces incremental effectiveness. Taking a payer perspective where payments from patients through drug copays or coinsurance are not included in the net cost to the payer, the incremental cost for tamsulosin versus terazosin is $388 for 20% coinsurance design and $184 for a tiered copay design (assuming $10 generic and $25 brand-name monthly drug copays). A lower rate of discontinuation increases incremental cost (mainly due to higher drug costs) but also improves effectiveness; a higher rate reduces both incremental costs and effectiveness. As the rate of twice-daily dosing (or 2 units per day) for all drugs increases, incremental effectiveness increases, but incremental costs also increase (due to higher drug costs). Thus, at 20% twice daily or 2 units per day dosing, the incremental cost per medical success using tamsulosin is $16,239, or about 11% higher than under the base-case assumption of no twice-daily or 2 units per day dosing. As noted in a "tornado" influence graph (Figure 2), removing commonly observed generic drug and brand-name drug patient copays from cost has the most significant impact on the estimated ICER because the higher brand-name copay ($25 per month) relative to the generic copay ($10 per month) significantly reduces the payer's incremental drug costs associated with the use of tamsulosin. The magnitude of the cost offset associated with avoiding or delaying TURP also has a substantial impact on the results. The assumed cost per hypotensive AE also affects estimated cost-effectiveness as does the assumed frequency of severe hypotensive AEs (fractures). The extent of twice-daily use and discontinuation rates are less influential.

ss Discussion
The model makes use of a simple construct of "successful medical therapy" as the primary measurement of treatment effectiveness. Although this measure is clinically relevant and intuitively appealing, its use entails important limitations in that some potentially relevant health benefits that accrue differentially across therapies may be missed in the analysis. For example, the model captures the cost impact of hypotensive episodes resulting in resource utilization, but there is no direct effect of such cases on the measure of treatment "effectiveness." However, it seems reasonable to suggest that, even if equally effective in treating BPH in terms of AUA symptom score, a therapy that results in even a small number of fractures from hypotension-related falls should be regarded as less effective overall than one that does not. A more refined measure of effectiveness would further enhance the cost-effectiveness analysis.
One way to achieve that goal would be to use utility ratings for health states to develop an estimate of incremental "cost per QALY" to compare with usual benchmarks. However, a 3-year time horizon may be too short to yield estimates appropriate for such comparisons, and utility measures for all potentially relevant health states are not readily available. Ackerman et al. 24 report utility decrements in the range of -0.025 to -0.073 for TURP as a surgical procedure and utility decrements in the range of -0.05 to -0.20 for TURP-related serious AEs. The model estimates that the initial tamsulosin strategy reduces the TURP rate by 4.5% and the rate of TURP-related serious AEs by 0.8% compared with the initial terazosin strategy. Given an incremental cost of about $610 over 3 years, a relatively modest increment in QALYs of 0.012 (or approximately 4.4 quality-adjusted days) would be needed to achieve the usual Cost-Effectiveness of Tamsulosin, Doxazosin, and Terazosin in the Treatment of Benign Prostatic Hyperplasia  benchmark of less than $50,000 per QALY for initial therapy with tamsulosin versus terazosin.
In the realm of drug treatments for BPH, there are no "league tables" for incremental costs per "successful medical treatment" of BPH symptoms. Cockrum et al. 13 define "treatment success" to include success achieved via TURP after medical therapy failure. No ICERs are reported in the Cockrum et al. paper, but using the reported cost and effectiveness estimates, the incremental cost per treatment success would be more than $3 million for initial treatment with finasteride versus prazosin (the only other nondominated strategy). This result is mainly attributable to a small denominator (incremental effectiveness) in the ICER, not a large numerator (incremental costs). In other words, if all who fail medical therapy progress to TURP, and TURP usually achieves treatment success in terms of AUA symptom score reduction, then almost all patients will achieve treatment "success" under this definition regardless of the initial treatment selected.
If an analogous effectiveness measure is used for the present analysis, the incremental cost per treatment success without TURP-related permanent adverse event is estimated to be about $84,000 for tamsulosin versus terazosin (Table 3). However, this effectiveness measure is not particularly sensitive to differences in potentially relevant outcomes across initial treatments.
Another important limitation of the analysis is the omission of any measures of indirect costs. Several prior studies (e.g., Lowe et al. 29 ) find that TURP is associated with potentially significant indirect costs compared with medical therapy. The model results indicate that tamsulosin is likely to be more effective in delaying TURP than terazosin or doxazosin. The potential impact of TURP-related indirect costs may be inferred by reference to the model scenario with the highest estimated cost for TURP, where incremental cost is estimated as $468 (versus $610 in the base case). Thus, a cost-effectiveness analysis where cost estimates include indirect costs would yield a lower estimated ICER.
As in any decision model, numerous simplifying assumptions were employed to maintain the transparency of the analysis. For example, no nonmedical treatment alternatives to TURP were considered in the analysis. Nonsurgical procedures such as microware thermotherapy may entail both lower cost and less risk than TURP. The lower TURP cost scenario presented in the sensitivity analyses provides some indication of the potential impact of including lower-cost alternatives to TURP in the model. Also, in usual clinical practice, many patients with moderate BPH who fail to attain a 25% improvement in symptoms on their initial therapy may choose to return to "watchful waiting" rather than progress to more aggressive treatment. Accounting for this possibility most likely would reduce both estimated costs and estimated effectiveness.
The analysis also did not consider newer extended-release forms of α-blockers as initial treatment strategies. Though data are lacking, it is possible that these therapies may entail a lower incidence of hypotensive AEs. However, as shown in Table 4, model results are not highly sensitive to assumed incidence rates or assumed cost per incident for hypotensive AEs. Because the treatment population considered in the model is not stratified by prostate size, the effectiveness of finasteride as a follow-up therapy among men with moderate BPH (in terms of baseline symptoms) but small prostates is likely to be overstated. Combination therapy (e.g., doxazosin and finasteride) also is not considered as an initial treatment strategy. Recent studies suggest that combination therapy may provide greater efficacy than either drug alone. 9,30 Although this strategy might entail greater effectiveness, it also would entail higher costs (due to higher drug costs-about $3.50 per day based on retaildiscounted prices).
Since all 3 drugs considered in the model usually are prescribed for once-daily dosing, for simplicity, the base-case model assumed no twice-daily or 2 units per day dosing. However, we also used a conservative assumption that actual use of these 3 α-blockers may be as much as 15% more than once-daily dosing. (Table 5) Thus, the model scenario assuming 15% twice-daily or 2 units per day dosing may reflect likely cost-effectiveness in usual clinical practice.

Cost-Effectiveness of Tamsulosin, Doxazosin, and Terazosin in the Treatment of Benign Prostatic Hyperplasia
Finally, although doxazosin is consistently dominated in the results above, estimated 3-year costs for terazosin relative to doxazosin are very sensitive to drug acquisition costs. Thus, any preference for generic terazosin versus generic doxazosin in the cost-effectiveness model would be based simply on lower drug acquisition costs under most circumstances.

ss Conclusions
A decision-model-based assessment of the costs and effectiveness of tamsulosin, terazosin, or doxazosin as initial therapies for BPH as used in clinical practice suggest that tamsulosin is both more effective and more costly than generic terazosin or doxazosin. In terms of cost-effectiveness, model estimates suggest incremental cost per treatment success ranges from about $84,000 for the most expansive definition of eventual treatment success to about $6,200 for a definition restricted to treatment success obtained by maintaining the initial drug therapy over 3 years. Most of the variation in incremental costeffectiveness across model scenarios results from differences in estimated effectiveness. Estimates of incremental cost consistently range from about $400 to $700 across a wide range of model scenarios. Thus, an incremental improvement of 0.008 to 0.014 QALYs (2.9 to 5.1 quality-adjusted days) would yield an incremental cost per QALY of $50,000 over a 3-year time period. Though it might be reasonable to speculate that lower rates of TURP and serious complications of therapy might yield these modest improvements in quality of life, additional research will be required to confirm or contradict this conjecture.

DISCLOSURES
Funding for this research was provided by Boehringer Ingelheim, Pharmaceuticals, Inc. (BIPI), the manufacturer of tamsulosin, and was obtained by author Robert L. Ohsfeldt. Ohsfeldt discloses that he has received funding from BIPI for projects through a contract with his employer, the University of Iowa; Author Robert W. Klein discloses that his employer, Medical Decision Modeling, Inc., receives contracts from BIPI; Author Karl J. Kreder is a speaker for BIPI; author Elizabeth A. Chrischilles discloses no potential bias or conflict of interest relating to this article.
Ohsfeldt served as principal author of the study. Study concept and design were contributed by Ohsfeldt, Kreder, and Klein. Analysis and interpretation of data were contributed by Kreder, Klein, and Chrischilles. Drafting of the "Tornado" Influence Diagram for One-Way Sensitivity Analyses (Base-Case Treatment Path)